PROJECT SUMMARY/ABSTRACT Pancreatic cancer continues to be a devastating disease with less than 10% 5-year survival. Pancreatic cancer is aggressive and there are no good tools for early detection. By the time of diagnosis, the tumor is often surgically unresectable. At this stage, patients are often treated with different chemotherapeutic agents or their combination, which while potent, have significant side-effects, limiting their dose. There is critical and an unmet need to selectively and precisely target the tumor only and deliver high doses of chemotherapy while sparing the surrounding healthy tissue from the deleterious effects of the chemotherapeutics. Pancreatic cancer cells depend on extracellular cystine/cysteine for growth and survival. The cystine molecules are transported into the pancreatic cancer cell through the xCT cystine transporter. Pancreatic cancer is characterized by an overexpression of surface xCT transporters compared to the healthy pancreas. Doric Pharma LLC?s patented drug delivery system uses targeted liposomal nanoparticles, TLNs, carry the anticancer drug as cargo and have specially designed surface molecules that target xCT transporters. Our studies show that TLNs selectively co- localize to pancreatic cancer cells in mice with orthotopic pancreatic tumors and reduce both orthotopic and subcutaneous pancreatic tumors. DoricPharma will examine if TLNs delivering gemcitabine spare other organs and tissues from its toxicity. In Aim 1 we will (a) characterize the physicochemical properties of TLNs loaded with gemcitabine and (b) determine the pharmacokinetics and biodistribution of gemcitabine encapsulated in TLNs after a single IV dose given to mice with orthotopic human pancreatic tumors. In Aim 2 we will determine the antitumor efficacy and reduced toxicity of gemcitabine encapsulated in TLNs for primary and metastatic tumors. We envision the TLNs system becoming a gold-standard for the delivery of chemotherapeutics because it selectively delivers anticancer drugs to cancer cells which improves activity and reduces toxicity. This Phase I STTR will determine if TLNs offer a superior and more efficacious treatment for pancreatic cancer. In addition, this project will position TLNs for IND- enabling studies (SBIR Phase II), after which DoricPharma LLC will seek partnerships for human phase I clinical trials. Overall, TLNs represent a paradigm shift for chemotherapy by selectively delivering agents to the tumor which will increase antitumor efficacy and reduce toxicity. Overall, TLNs will enhance the life span and the quality of life in cancer patients.